This application is a 371 of PCT/JP00/01021 filed Feb. 23, 2000.
The present invention relates to a novel process for industrially producing (aminomethyl)trifluoromethylcarbinol derivatives, in particular, optically active compounds thereof, which are useful as a starting compound for producing drugs.
(Aminomethyl)trifluoromethylcarbinol derivatives, in particular, optical active compounds thereof are important starting compounds for producing drugs such as protease inhibitors, etc., and some processes for producing the same have been reported.
For instance, JP-A-10-513173 (WO 96/23812) (hereinafter, occasionally referred to as Ref. 1) and J. Med. Chem., 40, 3173-3181 (1997) (hereinafter, occasionally referred to as Ref. 2) disclose the process as indicated in the Reaction Scheme (1) shown in FIG. 1 for producing (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol.
However, this process consists of many steps and further contains optical resolution steps, by which the total yield of the desired compound is low, and hence, this process is not suitable for industrial production.
The reaction conditions for each step:
(1) NaNO2, DMF;
(2) CF3CH(OH)OEt, K2CO3, t-BuOMe, fractional crystallization, distillation under reduced pressure;
(3) LiAlH4, Et2O;
(4) Triphosgen, NaOH;
(5) {circle around (1)} BuLi/THF, (xe2x88x92)-menthyl chloroformate;
{circle around (2)} Fractional crystallization;
(6) KOH
In addition, J. Med. Chem., 35, 641-662 (1992) (hereinafter, occasionally referred to as Ref. 3) discloses a process for producing (3S,2RS)-3-amino-4-phenyl-1,1,1-trifluoromethyl-2-butanol, which comprises obtaining N-t-butoxycarbonyl-L-phenylalaninal (aldehyde compound) from N-t-butoxycarbonyl-L-phenylalanine, followed by reacting the resultant with trimethyl(trifluoromethyl)silane (Ruppert reagent), as shown in the Reaction Scheme (2) shown in FIG. 2. However, it may be difficult to synthesize the intermediate for this process, i.e., an aldehyde compound, depending on the kinds of the amino acid, and when an amino acid having a large steric hindrance such as valine is used, the reaction with trimethyl(trifluoromethyl)silane cannot proceed. Therefore, this process cannot be a generally applicable process for producing (aminomethyl)trifluoromethylcarbinol derivatives.
As shown in the Reaction Scheme (3) shown in FIG. 3, J. Org. Chem., 63, 5179-5192 (1998) (hereinafter, occasionally referred to as Ref. 4) discloses that the 5-OH compound was synthesized starting from an optically active amino acid wherein the amino group is protected via the compound 1-8, and that said 5-OH compound could not be converted into a trifluoromethyl ketone compound by acid decomposition. In addition, there is no description as to the reduction of the 5-OH compound.
Further, WO 97/19681 (hereinafter, occasionally referred to as Ref. 5) illustrates in formula the synthesis of trifluoromethyl ketone compound starting from the compound 1-8 as shown in the Reaction Scheme (3). However, this literature does not disclose the conversion of the 5-OH compound into trifluoromethyl ketone compound. This literature merely indicates the synthesis of trifluoromethyl ketone compound by treating the 5-OH compound wherein the 2-position is substituted by 4-methylphenyl group or t-butyl group by ion-exchange resin.
The present inventors have intensively studied to find a process for industrially producing optically active (aminomethyl)trifluoromethyl-carbinol derivatives, and found that optically active (aminomethyl)-trifluoromethylcarbinol derivatives can surprisingly be obtained in high yield by reducing the 5-OH compound such as Compound 1b or 4b as shown the above Reaction Scheme (3), and further found that (aminomethyl)trifluoromethyl carbinol derivatives can be obtained easily in high yield by carrying out the reaction of each step of the above Reaction Scheme (3) starting from Compound 1-8 stepwise or in one-pot reaction, and have accomplished the present invention.
That is, the present invention provides novel processes for producing (aminomethyl)trifluoromethylcarbinol derivatives by the following Process A or Process B.
Process A of the present invention is a process for producing (aminomethyl)trifluoromethylcarbinol derivatives of the formula (I): 
wherein R1 is a group corresponding to the side chain of a natural or non natural xcex1-amino acid, R2 is a hydrogen atom or R21 (in which R21 is a protecting group for amino group having a carbonyl group at the binding site to the nitrogen atom), provided that when a functional group exists in R1, then such functional groups may optionally be protected,
or an acid addition salt thereof,
which comprises reducing a 5-hydroxy-5-trifluoromethyl-1,3-oxa-zolidine derivative of the formula (II) (hereinafter, occasionally referred to as the 5-hydroxy compound): 
wherein R1 and R21 are as defined above,
if necessary, removing a protecting group for amino group R21 from the product to give a compound of the formula (I) wherein R2 is a hydrogen atom, then followed by converting the product into an acid addition salt thereof, if necessary.
In addition, Process B of the present invention is a process for producing (aminomethyl)trifluoromethylcarbinol derivatives of the formula (I): 
wherein R1 and R2 are as defined above,
or an acid addition salt thereof,
which comprises carrying out the following Steps (a), (b) and (c) stepwise or by one-pot reaction, if necessary, removing a protecting group for amino group R21 from the product to give a compound of the formula (I) wherein R2 is a hydrogen atom, then followed by converting the product into an acid addition salt thereof, if necessary.
Step (a): Step of obtaining 5-trialkylsilyloxy-5-trifluoromethyl-1,3-oxazolidine derivative of the formula (IV) (hereinafter, occasionally referred to as the 5-trialkylsilyloxy compound); 
wherein R1 and R21 are as defined above,
by reacting a 1,3-oxazolidin-5-one derivative of the formula (III) (hereinafter, occasionally referred to as the 5-ketone compound): 
wherein R1 and R21 are as defined above,
with a trialkyl(trifluoromethyl)silane;
Step (b): Step of removing a trialkylsilyl group from the compound (IV) to give a 5-hydroxy compound of the formula (II): 
wherein R1 and R21 are as defined above; and
Step (c): Step of reducing the compound (II).
Further, the present invention provides an (aminomethyl)trifluoromethylcarbinol derivative of the formula (I): 
wherein R1 and R2 are as defined above,
or an acid addition salt thereof, which is produced by Process A or Process B.
The terms in the present description are explained below.
The xe2x80x9cgroup corresponding to the side chain of a natural or non-natural xcex1-amino acidxe2x80x9d defined by R1 means a group corresponding to the amino acid side chain of a naturally occurred or artificially synthesized xcex1-amino acid, i.e., a group obtained by removing a xe2x80x94CH(NH2)COOH moiety from an xcex1-amino acid, and when a functional group containing a nitrogen atom, an oxygen atom or a sulfur atom exists in said group, then said functional groups may be protected. The protecting group may be any one which does not disturb the production of the 5-hydroxy compound (II) either chemically, sterically and/or electronically.
Examples of the functional groups containing a nitrogen atom are an amino group, a mono-lower alkylamino group, a guanidino group, a 3-indolyl group, a 4-imidazolyl group, a 2-, 3- or 4-piperidyl group, a 3-morpholinyl group, a 2-piperazinyl group, etc.
Examples of the functional groups containing an oxygen atom are a hydroxy group, a carboxyl group, etc.
Examples of the functional groups containing a sulfur atom are a mercapto group, a sulfo group (xe2x80x94SO3H), etc.
For these functional groups, it is preferable to select ones being stable under conditions for removal of protecting group for amino group R21. Examples of the protecting groups are well known in this art, and can be easily selected by making reference to, for example, Protecting Group in Organic Synthesis, 2nd Ed. (Theodora W. Green, John Willy and Sons, Inc., 1991) (hereinafter, occasionally referred to as Ref. 6), etc.
The suitable examples of the xe2x80x9cgroup corresponding to the side chain of natural or non-natural xcex1-amino acidxe2x80x9d as defined by R1 are a lower alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group, and these groups may be substituted.
Examples of the xe2x80x9clower alkyl groupxe2x80x9d as R1 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc. Besides, in the present description, the term xe2x80x9clowerxe2x80x9d means a straight or branched carbon chain having 1 to 6 carbon atoms unless specified otherwise. Further, the substituent of the xe2x80x9clower alkyl groupxe2x80x9d includes, for example, 1 to 3 groups of hydroxy, mercapto, carboxyl, amino, mono-lower alkylamino, di-lower alkylamino, guanidino, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group. The xe2x80x9ccycloalkyl, aryl and heterocyclic groupxe2x80x9d and any substituents on these groups are explained below.
The xe2x80x9ccycloalkyl groupxe2x80x9d as R1 includes ones having 3 to 8 carbon atoms, and examples thereof are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and these groups may further optionally be substituted by 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group, phenyl, carboxyl, hydroxy, amino, a mono- or di-lower alkylamino, mercapto, etc.
The xe2x80x9caryl groupxe2x80x9d as R1 includes, for example, phenyl, naphthyl, etc., and these groups may further optionally be substituted by 1 to 3 groups selected from a halogen atom, trifluoromethyl, a lower alkyl group, a lower alkoxy group, an arylalkyloxy, phenyl, carboxyl, hydroxy, amino, a mono- or di-lower alkylamino group, etc.
The xe2x80x9cheterocyclic groupxe2x80x9d as R1 includes a monocyclic, bicyclic or tricyclic, saturated or unsaturated heterocyclic group having at least one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples of the heterocyclic group are furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, benzo[b]thienyl, benzo[b]furyl, indolyl, benzisoxazolyl, benzothiazolyl, quinolyl, dibenzothienyl, tetrahydrofuryl, tetrahydrothienyl, teterahydropyranyl, 1,3- or 1,4-dioxanyl, 1-piperazinyl, 1-morpholinyl, or 1-piperidinyl, etc. These xe2x80x9chetercyclic groupsxe2x80x9d may further optionally be substituted by 1 to 3 groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group, carboxyl group, etc.
More preferable examples of R1 are methyl, isopropyl, butyl, s-butyl, 4-aminobutyl, 3-guanidinopropyl, carboxymethyl, ethoxy-carbonylmethyl;, carbamoylmethyl, 2-carboxyethyl, 2-(methoxy-carbonyl)ethyl, 2-carbamoylethyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, benzyl, (4-hydroxyphenyl)methyl, (4-imidazolyl)methyl, (3-indolyl)methyl, and the groups as listed for R1 in the Table summarizing the products obtained in Examples 9-36, as described below.
When a functional group such as amino, guanidino, carboxyl, hydroxy and mercapto is contained in R1, then these functional groups are usually protected by a protecting group.
The xe2x80x9cprotecting group for amino group having a carbonyl group at the binding site to the nitrogen atomxe2x80x9d as defined by R21 may be any ones that are usually used in the chemical synthesis field, and it is preferably a group of the formula: xe2x80x94COR3. Then, R3 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkenyloxy group, an aryl group, an aryloxy group, an arylalkyl group, an arylalkyloxy group, a heteroaryl group, a heteroaryloxy group, or a lower alkoxy group, and these groups may be substituted or unsubstituted. The term xe2x80x9csubstituted or unsubstitutedxe2x80x9d used herein means that the group modified by this term may have a substituent being well known in the amino protection field.
Examples of the xe2x80x9clower alkyl groupxe2x80x9d as defined by R3 are ones as exemplified for R1, and examples of the alkenyl moiety of the xe2x80x9clower alkenyl groupxe2x80x9d or the xe2x80x9clower alkenyloxy groupxe2x80x9d are vinyl, allyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-methyl-1-propenyl, etc. These lower alkyl group, the lower alkenyl group and the lower alkenyloxy group used herein may optionally be substituted, for example, by 1 to 3 groups selected from a halogen atom and phenyl, etc.
Examples of the aryl moiety of the xe2x80x9caryl groupxe2x80x9d, the xe2x80x9caryloxy groupxe2x80x9d, the xe2x80x9carylalkyl groupxe2x80x9d and the xe2x80x9carylalkyloxy groupxe2x80x9d are ones as exemplified for R1, and these aryl moieties may optionally be substituted by 1 to 3 groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group, nitro, etc.
The heteroaryl moiety of the xe2x80x9cheteroaryl groupxe2x80x9d and the xe2x80x9cheteroaryloxy groupxe2x80x9d mean a monocyclic or bicyclic heteroaryl group having at least one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and examples thereof are furyl, thienyl, pyridyl, quinolyl, etc. These heteroaryl groups may optionally be substituted by 1 to 3 groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group, etc.
Examples of the alkyl moiety of the xe2x80x9clower alkoxy groupxe2x80x9d are ones as exemplified for R1, and these groups may optionally be substituted by 1 to 3 groups selected from a halogen atom, a trialkylsilyl group, a lower alkoxy, etc.
Examples of the xe2x80x9cprotecting group for amino group having a carbonyl group at the binding site to the nitrogen atomxe2x80x9d as defined by R21 are benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 2,4-dichlorobenzyloxycarbonyl group, t-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2-(trimethylsilyl)ethoxycarbonyl group, vinyloxycarbonyl group, allyloxycarboyl group, cinnamyloxycarbonyl group, 3,5-dimethoxyphenyloxycarbonyl group, formyl group, acetyl group, trichloroacetyl group, trifluoroacetyl group, phenylacetyl group, 3-phenylpropanoyl group, 3-butenoyl group, benzoyl group, 3-pyridyl-carbonyl group, etc. In view of the reactivity and workability, benzyl-oxycarbonyl group and t-butoxycarbonyl group are preferable.
Processes for producing (aminomethyl)trifluoromethylcarbinol derivatives of the present invention are illustrated in more detail.
Process A is carried out by treating the 5-hydroxy compound (II) with a reducing agent in a suitable solvent.
The reducing agent may be any one, which is inactive against the protecting group for amino group R21, and is suitable for reduction of ketonic carbonyl group into alcoholic hydroxy group. Examples of the reducing agent are metal borohydride reducing agents such as zinc borohydride, sodium borohydride, lithium borohydride, potassium borohydride, lithium triethyl borohydride, potassium triethyl boro-hydride, lithium tri-s-butyl borohydride, bis-methoxyethane lithium dimethylboron hydride, lithium boron hydride cyanide, sodium borocyanide hydride, etc. Among them, zinc borohydride, sodium borohydride, lithium borohydride, and potassium borohydride are preferable, and especially zinc borohydride and sodium borohydride are more preferable. However, zinc borohydride is unstable, and it is common to newly prepare zinc borohydride by contacting zinc chloride and sodium borohydride in ethers such as t-butyl methyl ether, diethyl ether, etc. when used.
The amount of the reducing agent may depend on the kinds of the reducing agent, and it is usually in the range of about 0.4 to about 4 equivalents, preferably about 1 equivalent, to the 5-hydroxy compound (II).
The solvent may be any one which does not disturb the reaction, and water; ethers such as t-butyl methyl ether, tetrahydrofuran, dimethoxyethane, dioxane, diglyme, etc.; alcohols such as methanol, ethanol, propanol, isopropanol, t-butanol, cyclohexanol, etc.; hydrocarbons such as benzene, toluene, hexane, cyclohexane, etc; dimethylformamide; dimethylsulfoxide; 1-methyl-2-pyrrolidinone, etc. These solvents may be used alone or in a mixture of two or more of the solvents. When zinc borohydride is used as a reducing agent, then the solvent is especially preferably t-butyl methyl ether.
The reaction temperature may depend on the kinds of the starting compounds, the kinds of the reducing agent, etc., but it is usually in the range of about xe2x88x9240xc2x0 C. to about 80xc2x0 C., preferably in the range of about 0xc2x0 C. to about 30xc2x0 C.
In this reaction, it is considered that the compound of the following formula (V) is first produced, and then converted into the compound (I). 
wherein R1 and R21 are as defined above.
When the conversion speed from the compound (V) into the compound (1) is slow, a basic substance or an acidic substance may be added to the reaction system in order to promote the conversion into the compound (I).
Examples of the acidic substance are inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, and organic acids such as acetic acid, trifluroacetic acid, methanesulfonic acid, trifluoro-methanesulfonic acid, p-toluenesulfonic acid, etc.
The basic substance may be either inorganic substances or organic substances.
Examples of the inorganic basic substances are ammonia, alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide), alkali metal phosphate or hydrogen phosphate (e.g., potassium phosphate, sodium hydrogen phosphate).
When a hardly soluble basic inorganic substance is used as a reaction solvent, it is preferable to add water or a phase transfer catalyst into the reaction system. Examples of the phase transfer catalyst are crown ethers such as 18-crown-6 or dibenzo-18-crown-6, or quaternary ammonium salt such as tetrabutylammonium hydogen sulfite, tetrabutyl ammonium bromide, etc.
Examples of the organic basic substances are primary amines (e.g., methylamine, ethylamine, propylamine, benzylamine), secondary amines (e.g., dimethylamine, ethylmethylamine, benzylmethylamine), tertiary amines (e.g., triethylamine, ethyldiisopropylamine, N-methyl-morpholine, 1,8-diazobicyclo[5.4.0]-7-undecene (DBU), pyridine, 2,4,6-trimethylpyridine, 2,6-di(t-butyl)pyridine), alkali metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide, lithium t-butoxide, potassium t-butoxide), alkali metal salts of organic acid (e.g., sodium acetate), etc.
The amount of the basic substance or acid substance for accelerating the conversion speed from the compound (V) to the compound (I) should be determined according to the kinds of the protecting group for amino group R21 and the kinds of the basic substance or acid substance to be used, and it is usually in the range of about 1 equivalent to about 10 equivalents to the compound (II).
The reaction temperature is usually in the range of about 0xc2x0 C. to about 40xc2x0 C., and preferably room temperature. The reaction time may vary according to the conversion speed from the compound (V) to the compound (I), and it is usually in the range of about 1 to about 12 hours. In view of the workability, a basic substance is more preferable than an acidic substance, and in view of the practicability, potassium carbonate is preferable.
The compound (I) thus obtained wherein R2 is R21 (i.e., a protecting group for amino group) can be converted in a high yield into the compound (I) wherein R2 is a hydrogen atom by removing said protecting group for amino group by a conventional method. The conditions for removal of said protecting group for amino group are preferably selected so as not to remove a protecting group for a functional group which may optionally exist in R1. Because, it is more advantage that such protecting group for functional group is not removed in this stage but removed in the stage of production of a final product such as protease inhibitor, etc.
The compound (I) wherein R2 is a hydrogen atom can be converted into an acid addition salt thereof by treating it with an inorganic acid or organic acid by a conventional method.
The starting compound (II) of Process A can be prepared by the method disclosed, for example, Ref. 1 (J. Org. Chem., 63, 5179-5192 (1998)) or Ref. 5 (WO 97/19681) or a modified method thereof. In addition, the compound (II) can also be prepared by carrying out Step (a) and Step (b) of the following Process B stepwise or by one-pot reaction.
Process B is effected by carrying out the following Steps (a), (b) and (c) sequentially stepwise or consecutively in one-pot reaction. xe2x80x9cCarrying out sequentially stepwisexe2x80x9d means isolating a product obtained in each step, then using said product in a subsequent step as a starting compound and reacting it. On the contrary, xe2x80x9ccarrying out consecutively in one-pot reactionxe2x80x9d means carrying out consecutively all steps in one reaction vessel without isolating a product from each step as post treatment of each step.
Step (a):
This is a step of reacting the starting 5-ketone compound (III) with a trialkyl(trifluoromethyl)silane to give a 5-trialkylsilyloxy compound (IV).
Three alkyl groups of the trialkyl(trifluoromethyl)silane used in this step may be either the same or different, and the trialkyl(trifluoro-methyl)silane includes, for example, trimethyl(trifluoromethyl)silane, triethyl(trifluoromethyl)silane, tributyl(trifluoromethyl)silane, etc., and trimethyl(trifluoromethyl)silane is preferable. These compounds may be commercially available or prepared by a method disclosed in Org. Synth., 72, 232-240 (hereinafter, occasionally referred to as Ref. 7) or in J. Org. Chem., 54, 2873-2877 (1989) (hereinafter, occasionally referred to as Ref. 8) or a modified method thereof.
This step (a) is carried out by mixing and stirring the 5-ketone compound (III) and a trialkyl(trifluoromethyl)silane in the presence of a nucleophilic reaction initiating reagent in a suitable solvent. The solvent may be ethers (e.g., tetrahydrofuran, dimethoxyethane, dioxane, etc.), aromatic hydrocarbons (e.g., benzene, toluene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), etc. These solvents may be used alone or in a mixture of two or more of the solvents, and ethers are more preferable.
The nucleophilic reaction initiating reagent may be ones disclosed in Chem. Rev., 97, 757-786 (1997) (hereinafter, occasionally referred to as Ref. 9), and cesium fluoride and tetrabutylammonium fluoride are preferable, and cesium fluoride is especially preferable.
The amount of the trialkyl(trifluoromethyl)silane to the amount of the 5-ketone compound (III) is usually in the range of about 1 equivalent to about 2 equivalents, and the amount of the nucleophilic reaction initiating reagent to the amount of the 5-ketone compound (III) is usually in the range of about 0.1 equivalent to about 0.3 equivalent. The reaction temperature is usually in the range of about xe2x88x9220xc2x0 C. to about 60xc2x0 C., preferably in the range of about 0xc2x0 C. to about 30xc2x0 C. The reaction time may vary according to the kinds of the compounds, and it is usually in the range of about 20 minutes to about 30 minutes.
The starting 5-ketone compound (III) may be prepared from easily available starting xcex1-amino acids having an amino group protected by a conventional well known method, for example, by the method disclosed in Ref. 4 (J. Org. Chem., 63, 5179-5192 (1998)), Ref. 5 (WO 97/19681), J. Am. Chem. Soc., 79, 5736-5738 (1957) (hereinafter, occasionally referred to as Ref. 10), or in Reference Example 1 described hereinbelow, or a modified method thereof,
Step (b):
This is a step of de-silylization of the 5-trialkylsilyloxy compound (IV) obtained in the above step to give a 5-hydroxy compound (II).
This step can easily be carried out by adding an excess amount of an alcohol into the reaction solution after the completion of Step (a). The alcohol may be methanol, ethanol, isopropanol, etc. These alcohols can be used alone or in a mixture of two or more of the solvents. The reaction temperature is usually in the range of about 0xc2x0 C. to about 70xc2x0 C., preferably in the range of about 10xc2x0 C. to about 50xc2x0 C.
Step (c):
This is a step of reducing the 5-hydroxy compound (II) obtained in the above step to give the desired compound (II), and can be carried out in the same manner as in Process A.
Among the desired compounds (I) thus obtained, the compound (I) wherein R2 is R21 (i.e., a protecting group for amino group) can be converted in high yield into the compound (I) wherein R2 is a hydrogen atom by removing said protecting group for amino group by a conventional method. The conditions for removal of the protecting group for amino group are preferably selected so as not to remove a protecting group for a functional group which may exist in R1.
The compound (I) wherein R2 is a hydrogen atom can be converted into an acid addition salt thereof by treating it with an inorganic acid or organic acid by a conventional method.
According to Process A or B of the present invention, the desired compound (I) can be obtained with keeping the configuration of the carbon atom at the 4-position of the 5-hydroxy compound (II) or the 5-ketone compound (III). Therefore, from the 5-hydroxy compound (II) or the 5-ketone compound (III) wherein the configuration of the carbon atom at the 4-position is R-, S- or RS-configuration, there is obtained the compound (I) wherein the configuration of the asymmetric carbon atom to which R1 bonds is R-, S- or RS-configuration, respectively. With respect to the asymmetric carbon atom to which the hydroxy group bonds in the formula (I), there are obtained the compound (I) having a single configuration or the compound (I) in a mixed configuration, owing to the kinds of R1. When the compound (I) is obtained in the form of a mixture, one of the stereoisomers is preferentially produced. For example, as shown in the Reaction Scheme (4) shown in FIG. 4, when the desired compound (I-a) is obtained from (4S)-4-isopropyl-5-oxo-1,3-oxazolidine-3-carboxylic acid benzyl ester (III-a) as a starting compound, which is prepared from N-benzyloxycarbonyl-L-valine by the method of Reference Example 1,N-[(1S,2S)-3,3,3-trifluoro-2-hydroxy-1-(isopropyl)propyl]carbamic acid benzyl ester (I-a) having both of two asymmetric carbon atoms in S-configuration is preferentially produced. Therefore, the desired compound preferentially produced is purified into a pure form by a conventional method such as chromatography, recrystallization, reprecipitation, etc.
In addition, the determination of the absolute structure of the asymmetric carbon atom to which the hydroxy group bonds of the compound (I-a) in Reaction Scheme (4) is explained in Example 43 as mentioned below.
The hydroxy group of the compound (I) can be converted into a carbonyl group by oxidization when a final product being useful as a protease inhibitor, etc. is produced. Therefore, as far as the configuration of the asymmetric carbon atom to which R1 bonds is desirable one, the stereoisomer due to the asymmetric carbon atom to which the hydroxy group bonds is practically acceptable even though it is in the form of a mixture.
In the present description, the following abbreviations having the following meanings are occasionally used.